The outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infections poses a threat to public health worldwide. Although the predicted pandemic potential of MERS remains low, an increase in the sustainability of human-to-human transmission, as a result of further evolution of MERS-CoV in nature, is of concern. To date, neither the pathogenesis nor effective intervention against this newly emerged human disease is available, largely due to the lack of animal species, especially, the small laboratory species that can recapitulate clinical illness in response to infection. Understanding the mechanism used by MERS-CoV to cause diseases in suitable animal models can help in identifying novel targets for the development of effective therapeutics. While nonhuman primates (NHP) (i.e., rhesus macaques) are permissive to MERS-CoV, the infection in NHPs results in the onset of acute, but self-resolving, respiratory stress without any mortality. Moreover, the high cost, varying degrees of histopathology, and the nature of transient and limited clinical illness make this model less attractive, especially for testing vaccines and therapeutics. Development of animal models has recently been listed as a prioritized area of MERS-CoV research by NIH/NIAID. Our laboratory has previously reported that mice which are inheritably resistant to clinical illness associated with SARS-CoV infection became fully permissive to the virus, resulting in morbidity and mortality, when expressing human ACE2 viral receptor. Based on our prior success, we propose establishing transgenic mice expressing the human CD26/DPPIV (hCD26) viral receptor as the small animal model for MERS-CoV. As the expression of hCD26 is not restricted to the lungs, we will generate transgenic mouse lineages with either constitutive (Aim 1) or lung-specific expression of hCD26 (Aim 2) in this application, as an alternative to the existing NHP model. Successful establishment of these transgenic mouse models will be useful not only for studying morbidity, mortality, and viral replication in humans, but also for evaluating preventive and therapeutic agents developed against MERS-CoV.